In our study, we found that CD74 was the most upregulated gene in the identified exhausted CD8+T cell subcluster and played a suppressive role in CD8+T cell function and survival and that deregulation of CD74 by interfering with the expression of NSUN4 decreased tissue infiltration and the proportion of circulating CD7highCD74high CD8+T cells, serum contents of autoimmune antibodies, and tissue damage of the skin and kidney in SLE mice. This evidence concerns the gene NSUN4 and systemic lupus erythematosus.